Evolution of the human cold/menthol receptor, TRPM8

Mol Phylogenet Evol. 2019 Jul;136:104-118. doi: 10.1016/j.ympev.2019.04.011. Epub 2019 Apr 10.


Genes showing versatile functions or subjected to fast expansion and contraction during the adaptation of species to specific ecological conditions, like sensory receptors for odors, pheromones and tastes, are characterized by a great plasticity through evolution. One of the most fascinating sensory receptors in the family of TRP channels, the cold and menthol receptor TRPM8, has received significant attention in the literature. Recent studies have reported the existence of TRPM8 channel isoforms encoded by alternative mRNAs transcribed from alternative promoters and processed by alternative splicing. Since the first draft of the human genome was accomplished in 2000, alternative transcription, alternative splicing and alternative translation have appeared as major sources of gene product diversity and are thought to participate in the generation of complexity in higher organisms. In this study, we investigate whether alternative transcription has been a driving force in the evolution of the human forms of the cold receptor TRPM8. We identified 33 TRPM8 alternative mRNAs (24 new sequences) and their associated protein isoforms in human tissues. Using comparative genomics, we described the evolution of the human TRPM8 sequences in eight ancestors since the origin of Amniota, and estimated in which ancestors the new TRPM8 variants originated. In order to validate the estimated origins of this receptor, we performed experimental validations of predicted exons in mouse tissues. Our results suggest a first diversification event of the cold receptor in the Boreoeutheria ancestor, and a subsequent divergence at the origin of Simiiformes.

Keywords: Alternative transcription; Bioinformatics; Cold and menthol receptor; Evolution; Isoforms; Phylogenetics; Splice variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Animals
  • Cell Line, Tumor
  • Cold Temperature*
  • Evolution, Molecular*
  • Exons / genetics
  • Genetic Variation
  • HEK293 Cells
  • Humans
  • Menthol / metabolism*
  • Mice
  • Open Reading Frames / genetics
  • Phylogeny
  • Protein Isoforms / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • TRPM Cation Channels / genetics*
  • TRPM Cation Channels / metabolism


  • Protein Isoforms
  • RNA, Messenger
  • TRPM Cation Channels
  • TRPM8 protein, human
  • TRPM8 protein, mouse
  • Menthol